Infection with respiratory viruses, such as with influenza, coronavirus, and others, results in considerable pulmonary immunopathology, a large component of which results from the host specific immune responses,. Type 1 interferons (IFN-a(3) represent an important component of the innate immune response to most virus infections, and most strains of virus, including the highly pathogenic strains of influenza, have evolved mechanisms to suppress or evade these defenses. In addition to the direct inhibition of viral replication, type 1 interferons possess a variety of other immunomodulatory properties. Recently, however, it has become apparent that lung injury which occurs in the context of the T cell response to experimental influenza infection is considerably more severe in the absence of the IFN-a(3 receptor, and this is not a result of enhanced viral replication. Our data indicate that expression of the inhibitory NKG2A receptor on CD8+ T cells, which is usually induced during the course of viral clearance, is not significantly induced in the absence of the IFN-a3-receptor. Furthermore, the activation threshold of CD8+ T cells is increased by NKG2A activity, and when NKG2A binding to its cognate receptor is blocked, enhanced T cell effector activity is observed. Examination of the requirements for induction of inhibitory NKG2A expression by CD8+ T cells in influenza infection suggests that initial antigen recognition in the presence of IFN-a(3 in the regional lymph node is probably required, though expression is not observed until the cells reach the effector site in the periphery (i.e. the lung parenchyma). In order to understand the role of type 1 interferons on the inhibition of pulmonary immunopathology in respiratory virus infection, we will test the hypothesis that initial antigen engagement in the presence of type 1 interferon results in "priming" for CD8+ T cell inhibitory NKG2A expression, but that actual receptor expression on CD8+ T cells requires antigen recognition in the lung parenchyma, probably on professional antigen-presenting cells such as dendritic cells. Specifically we propose to analyze the direct and indirect effects of type I interferon on regulation of CD8+ T cell NKG2A expression and immunopathologic potential, and to understand the mechanisms of regulation of CD8+ T cell NKG2A expression by IFN-a(3. This will shed important light into the mechanisms of fine-tuning of the antiviral adaptive immune responses to optimize virus clearance and minimize tissue damage which may occur in the process.
Influenza infection results in considerable damage to infected tissues, and this becomes of paramount importance with infection of the lower respiratory tract, i.e. pneumonia, which is common with highly pathogenic strains. Understanding the fine regulation of antiviral immune responses and the ways in which these responses cause or limit lung injury will be of enormous benefit in designing rational therapies.
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